Biodegradable medical implant with encapsulated buffering agent

ABSTRACT

A medical device for placement at a site in a patient&#39;s body and for controlling pH levels at the site in the patient&#39;s body includes one or more structural components made of a first biodegradable and/or bioabsorbable material or, alternatively, one or more structural components having a coating thereon made of a first biodegradable and/or bioabsorbable material. The device also includes a buffering agent and at least one second biodegradable and/or bioabsorbable material on or in the one or more structural components, or alternatively, on or in the coating on the one or more structural components. The at least one second biodegradable and/or bioabsorbable material encapsulates the buffering agent and the buffering agent is dispersed from the at least one second biodegradable and/or bioabsorbable material in response to hydrolysis of the first biodegradable and/or bioabsorbable material. Additionally, the device can include a drug that is either also encapsulated by the at least one second biodegradable and/or bioabsorbable material or is included with the first biodegradable and/or bioabsorbable material.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates, in general, to implantable medicaldevices, and, in particular, to new and useful bioabsorbable medicaldevices that are capable of being a self-regulating system forcontrolling the acidic effects of degradation. Additionally, the presentinvention relates, in particular, to bioabsorbable medical devices forvascular or cardiovascular applications that can control the acidiceffects of degradation.

Bioabsorbable implants are typically made from polymeric materials suchas lactone-based polyesters. These bulk eroding materials breakdown overtime due to chemical hydrolysis to produce water-soluble, low molecularweight fragments. These fragments are then attacked by enzymes toproduce lower molecular weight metabolites. Acid fragments that areproduced during degradation of the polymer backbone have shown to causelocal tissue inflammation. The inflammation has been observed invascular systems as well and the extent of inflammation depends on thepH of the acid that in turn is dependent on the type and amount of acidproduced during degradation. This inflammation is not typically observedin polymers that degrade by surface erosion (such as polyorthoesters andpolyanhydrides) as the amount of acid released at a given time is smallto cause tissue inflammation.

Additionally, most of the past research in the field of bioabsorbableimplants has been directed toward orthopedic applications, for instance,toward using a bioabsorbable implant as internal fixation devices inbone. Thus, this trend is specifically toward internal fixation devicesfor repair of damaged bone through the use of resorbable, tissuecompatible biopolymers. Biopolymers such as poly(glycolic acid) [PGA],poly(lactide) [PLA], and copolymers of lactic and glycolic acids,[poly(lactide-co-glycolide) or PLGA] have been used in the production ofinternal fixation devices, such as screws, pins, and rods to hold bonetogether following surgery, or to repair broken bones. Other polymers,such as poly(dioxanone), have also been considered for use in themanufacture of surgical internal fixation devices. However, it has beenobserved that tissue response to resorbable implants fabricated fromthese biopolymers is not uniformly acceptable (Bostman, J. Bone andJoint Surg. 73, 148-153 (1991).

The tissue response to these biopolymer-based orthopedic implants hasbeen well documented. Late sterile inflammatory foreign body response(sterile abscess) has been reported in about 8% of fractures repairedwith these polymers (Bostman, supra). In a randomized study of 56 openreduction and internal fixation of malleolar fractures of the ankle withmetal ASIF screws and plates or with rods of PLGA, two cases of sterileinflammatory wound sinus were observed 3 to 4 months after the operationin the injuries fixed with the polymer rods (Rokkanen et al., Lancet 1,1422-1425 (1985); Bostman et al., J. Bone and Joint Surg., 69-B(4),615-619 (1987)).

Other orthopedic studies have also documented an inflammatory reactionfollowing implantation of PGA or PLGA orthopedic fixation devices. Thefraction of patients suffering from this reaction ranges from 4.6 to22.5% (Bostman et al., Clin. Orthop. 238, 195-203 (1989); Bostman etal., Internat. Orthop. 14, 1-8 (1990); Hirvensalo et al., Acta Orthop.Scandinavica, Supplementum 227, 78-79 (1988); Hoffman et al.,Unfallchirurgie 92, 430-434 (1989); Partio et al., Acta Orthop.Scandinavica, Supplementum 237, 43-44 (1990); Bostman et al., Internat.Orthop. 14, 1-8 (1990)).

Moreover, the inflammatory reaction is not limited to orthopedicimplants made from poly(glycolide) polymers. Internal fixation devicesmade from poly(lactide) have also been observed to exhibit aninflammatory reaction. Eitenmuller et al. reports that 9 of 19 patients(47.7%) who had fractures of the ankle treated with absorbable platesand screws of poly(lactide) had an inflammatory response. (J.Eitenmuller, A. David, A. Pomoner, and G. Muhyr: “Die Versorgung vonSprunggelenlzsfrakturen unter Verwendung von Platten und Schrauben ausresorbserbarem Polymermaterial”, Read at Jahrestagung der DeutschenGesellschaft fur Unfallheilkunde, Berlin, Nov. 22, 1989).

Additionally, in vitro studies have been performed to monitor pH changesas well as weight loss and the appearance of lactic acid from orthopedicscrews fabricated from poly(lactide-co-glycolide) with alactide:glycolide ratio of 85:15. (Vert et al., J. Controlled Release16, 15-26 (1991)). An induction period of about ten weeks was observedbefore any significant change in media pH or weight loss occurred. Thistime period corresponds to the induction periods of seven to twentyweeks noted by orthopedic clinicians. However, no attempt had been madeto alleviate the source of inflammation.

One known in vitro study involving orthopedic implants is described in JBiomed Mater Res (Appl Biomater) 38: 105-114, 1997 and was performed toexamine if the pH decrease in the vicinity of degrading polylactic acid(PLA) and polyglycolic acid (PGA) polymers could be offset byincorporation of basic salts within PLA-PGA orthopedic implants. It hadbeen suggested that such pH lowering results in adverse effects, whichmay be responsible for biocompatibility concerns raised recently aboutPLA and PGA polymers. Accordingly, this study was conducted and theresults indicated that all three salts investigated in this study weresuccessful in controlling the decrease in pH due to the acidicdegradation products of the copolymer. The pH of the test media for thecontrol group fell to a value of 3.0 at 9 weeks. Implants containingcalcium carbonate maintained the pH value between 7.4 and 6.3 throughoutthe degradation process. Implants with calcium hydroxyapatite and sodiumbicarbonate controlled the pH values between 6.9 and 4.3 and 8.2 and4.5, respectively. At 3 weeks, marked swelling of implants containingcalcium carbonate or sodium bicarbonate was observed relative to thecontrol orthopedic implants. The molecular weight and mass changes inthe orthopedic implants did not show any significant differences at 9weeks. Thus, results from this in vitro study showed that a significantdecrease in pH in the vicinity of a PLA-PGA orthopedic implant could beavoided by incorporating basic salts into the orthopedic implant itself.

To date, there have been no known bioabsorbable medical devices that arecapable of being a self-regulating system for controlling the acidiceffects of degradation. Additionally, to date, there have been no knownbioabsorbable medical devices for vascular or cardiovascularapplications that can control the acidic effects of degradation.

SUMMARY OF THE INVENTION

The present invention relates to medical devices that are placed orimplanted in the body including medical devices that are placed invessels such as an artery or a vein or ducts or organs such as theheart. Particularly, the present invention is a medical device that iseither made of biodegradable and/or bioabsorbable material or is coatedwith biodegradable and/or bioabsorbable material for helping to suppressinflammation and the effects of inflammation and, in some embodiments,for efficaciously delivering a therapeutic agent.

The present invention is a biodegradable and/or bioabsorbable medicaldevice for placement or implantation in a patient's body, wherein themedical device is a self-regulating system for controlling the acidiceffects of degradation. Additionally, the biodegradable and/orbioabsorbable medical device in accordance with the present invention isa device designed for placement within a vessel or duct, and moreparticularly, vasculature such as an artery or vein, as well as forplacement on, within or into an organ, and more particularly, a portionof the heart and can control the acidic effects of degradation. Evenmore particularly, the present invention is a medical device that is adevice for vascular or cardiovascular use such as a stent or valve cancontrol the acidic effects of degradation.

In some embodiments, the present invention is a medical device forplacement at a site in a patient's body and for controlling pH levels atthe site in the patient's body and comprises one or more structuralcomponents made of a first biodegradable and/or bioabsorbable materialor, alternatively, one or more structural components having a coatingthereon made of a first biodegradable and/or bioabsorbable material. Thedevice also comprises a buffering agent and at least one secondbiodegradable and/or bioabsorbable material on or in the one or morestructural components, or alternatively, on or in the coating on the oneor more structural components. The at least one second biodegradableand/or bioabsorbable material encapsulates the buffering agent and thebuffering agent is dispersed from the at least one second biodegradableand/or bioabsorbable material in response to hydrolysis of the firstbiodegradable and/or bioabsorbable material. Additionally, the devicecan include a drug that is either also encapsulated by the at least onesecond biodegradable and/or bioabsorbable material or is included withthe first biodegradable and/or bioabsorbable material.

In other embodiments, the present invention is a vascular orcardiovascular medical device for placement at a site in a patient'sbody and for controlling pH levels at the site in the patient's body andcomprises one or more structural components made of a biodegradableand/or bioabsorbable material, or alternatively, a coating thereon madeof a biodegradable and/or bioabsorbable material. A buffering agent isprovided on or in the biodegradable and/or bioabsorbable material andthe buffering agent is dispersed from the biodegradable and/orbioabsorbable material in response to hydrolysis of the biodegradableand/or bioabsorbable material. Additionally, the vascular orcardiovascular medical device can include a drug that is included withthe biodegradable and/or bioabsorbable material. The vascular orcardiovascular medical device can also be a stent or a valve.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. The invention itself, however, both as toorganization and methods of operation, together with further objects andadvantages thereof, may be understood by reference to the followingdescription, taken in conjunction with the accompanying drawings inwhich:

FIG. 1 is a schematic illustration of a medical device having a firstbiodegradable and/or bioabsorbable material and a second biodegradableand/or bioabsorbable material, shown as a cross-sectional slice takenfrom a sphere, whose degradation is triggered by degradation productsproduced by degrading of the first biodegradable and/or bioabsorbablematerial in accordance with the present invention;

FIG. 2 is a schematic illustration of a portion of structure or coatingthat can be used for the medical device of FIG. 1 wherein the structureor coating has a second biodegradable and/or bioabsorbable material,shown as a cross-sectional slice taken from a sphere, encapsulating abuffering agent in accordance with the present invention;

FIG. 3 is a schematic illustration of a portion of structure or coatingthat can be used for the medical device of FIG. 1 wherein the structureor coating includes a drug and has a second biodegradable and/orbioabsorbable material, shown as a cross-sectional slice taken from asphere, encapsulating a buffering agent in accordance with the presentinvention;

FIG. 4 is a schematic illustration of a portion of structure or coatingthat can be used for the medical device of FIG. 1 wherein the structureor coating has a second biodegradable and/or bioabsorbable material,shown as a cross-sectional slice taken from a sphere, encapsulating botha buffering agent and a drug in accordance with the present invention;

FIG. 5 is a schematic illustration of a portion of structure or coatingthat can be used for the medical device of FIG. 1 wherein the structureor coating has a buffering agent in accordance with the presentinvention;

FIG. 6 is a schematic illustration of a portion of structure or coatingthat can be used for the medical device of FIG. 1 wherein the structureor coating has a buffering agent and a drug in accordance with thepresent invention; and

FIG. 7 is a graph illustrating pH levels over time based on degradationof the medical device of FIG. 1 in accordance with the presentinvention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to medical devices that are placed orimplanted in the body including medical devices that are placed invessels such as an artery or a vein or ducts or organs such as theheart. Particularly, the present invention is a medical device that iseither made of bioabsorbable material or is coated with bioabsorbablematerial for helping to suppress inflammation and the effects ofinflammation and, in some embodiments, for efficaciously delivering atherapeutic agent.

As used herein, the terms “biodegradable”, “degradable”, “degradation”,“degraded”, “bioerodible”, “erodible” or “erosion” are usedinterchangeably and are defined as the breaking down or thesusceptibility of a material or component to break down or be brokeninto products, byproducts, components or subcomponents over time such asdays, weeks, months or years.

As used herein, the terms “bioabsorbable”, “absorbable”, “resorbable”and “bioresorbable” are used interchangeably and are defined as thebiologic elimination of any of the products of degradation by metabolismand/or excretion.

As used herein, the terms “buffering agent”, “buffering compound”,“buffer”, “neutralizing agent”, “neutralizing compound”, “neutralizationagent”, or “neutralization compound” are used interchangeably anddefined as any material, agent, compound or substance that limits ormoderates the rate of change of the pH of a medical device or the localor near environment of the medical devices upon exposure to acid orbase.

As used herein, the term “acid”, “acid components”, “acid products”,“acid byproducts”, “acidic”, “acidic products”, “acidic components” or“acidic byproducts” are used interchangeably and are defined as anyproduct that generates an aqueous solution or environment with a pH lessthan 7.

As used herein, the term “composite”, “biodegradable material”,“biodegradable polymer”, “bioabsorbable material”, “bioabsorbablepolymer” “biodegradable and/or bioabsorbable material” or “biodegradableand/or bioabsorbable polymer” are used interchangeably and are definedas any polymer material that is biodegradable or bioabsorbable in thebody.

As used herein, the terms “agent”, “therapeutic agent”, “active agent”,“drug”, “active drug”, and “pharmaceutical agent” are usedinterchangeably herein and define an agent, drug, compound, compositionof matter or mixture thereof which provides some therapeutic, oftenbeneficial, effect. This includes pesticides, herbicides, germicides,biocides, algicides, rodenticides, fungicides, insecticides,antioxidants, plant growth promoters, plant growth inhibitors,preservatives, antipreservatives, disinfectants, sterilization agents,catalysts, chemical reactants, fermentation agents, foods, foodsupplements, nutrients, cosmetics, drugs, vitamins, sex sterilants,fertility inhibitors, fertility promoters, microorganism attenuators andother agents that benefit the environment of use. As used herein, theterms further include any physiologically or pharmacologically activesubstance that produces a localized or systemic effect or effects inanimals, including warm blooded mammals, humans and primates; avians;domestic household or farm animals such as cats, dogs, sheep, goats,cattle, horses and pigs; laboratory animals such as mice, rats andguinea pigs; fish; reptiles; zoo and wild animals; and the like. Theactive drug that can be delivered includes inorganic and organiccompounds, including, without limitation, drugs which act on theperipheral nerves, adrenergic receptors, cholinergic receptors, theskeletal muscles, the cardiovascular system, smooth muscles, the bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system and the centralnervous system. Suitable agents may be selected from, for example,proteins, enzymes, hormones, polynucleotides, nucleoproteins,polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids,hypnotics and sedatives, psychic energizers, tranquilizers,anticonvulsants, muscle relaxants, antiparkinson agents, analgesics,anti-inflammatories, local anesthetics, muscle contractants, bloodpressure medications and cholesterol lowering agents including statins,antimicrobials, antimalarials, hormonal agents including contraceptives,sympathomimetics, polypeptides and proteins capable of elicitingphysiological effects, diuretics, lipid regulating agents,antiandrogenic agents, antiparasitics, neoplastics, antineoplastics,hypoglycemics, nutritional agents and supplements, growth supplements,fats, ophthalmics, antienteritis agents, electrolytes and diagnosticagents.

Examples of the therapeutic agents or drugs 99 useful in this inventioninclude prochlorperazine edisylate, ferrous sulfate, aminocaproic acid,mecaxylamine hydrochloride, procainamide hydrochloride, amphetaminesulfate, methamphetamine hydrochloride, benzphetamine hydrochloride,isoproteronol sulfate, phenmetrazine hydrochloride, bethanecholchloride, methacholine chloride, pilocarpine hydrochloride, atropinesulfate, scopolamine bromide, isopropamide iodide, tridihexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride,theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperazine maleate, anisindione, diphenadione, erythrityltetranitrate, digoxin, isoflurophate, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chiormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, hydrocortisone, hydrocorticosterone acetate, cortisoneacetate, dexamethasone and its derivatives such as betamethasone,triamcinolone, methyltestosterone, 17-.beta.-estradiol, ethinylestradiol, ethinyl estradiol 3-methyl ether, prednisolone,17-.beta.-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, indomethacin, naproxen, fenoprofen,sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol,timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine,levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine,theophylline, calcium gluconate, ketoprofen, ibuprofen, atorvastatin,simvastatin, pravastatin, fluvastatin, lovastatin, cephalexin,erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine,phenoxybenzamine, diltiazem, milrinone, captropril, mandol, quanbenz,hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen,tolmetin, alclofenac, mefenamic, flufenamic, difuninal, nimodipine,nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine,tiapamil, gallopamil, amlodipine, mioflazine, lisinopril, enalapril,captopril, ramipril, enalaprilat, famotidine, nizatidine, sucralfate,etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam,amitriptylin, and imipramine. Further examples are proteins and peptideswhich include, but are not limited to, insulin, colchicine, glucagon,thyroid stimulating hormone, parathyroid and pituitary hormones,calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone,follicle stimulating hormone, chorionic gonadotropin, gonadotropinreleasing hormone, bovine somatotropin, porcine somatropin, oxytocin,vasopressin, prolactin, somatostatin, lypressin, pancreozymin,luteinizing hormone, LHRH, interferons, interleukins, growth hormonessuch as human growth hormone, bovine growth hormone and porcine growthhormone, fertility inhibitors such as the prostaglandins, fertilitypromoters, growth factors, and human pancreas hormone releasing factor.

Moreover, drugs or pharmaceutical agents 99 useful for the medicaldevice 50 include: antiproliferative/antimitotic agents includingnatural products such as vinca alkaloids (i.e. vinblastine, vincristine,and vinorelbine), paclitaxel, epidipodophyllotoxins (i.e. etoposide,teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin,doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins,plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase whichsystemically metabolizes L-asparagine and deprives cells which do nothave the capacity to synthesize their own asparagine); antiplateletagents such as G(GP)II_(b)III_(a) inhibitors and vitronectin receptorantagonists; antiproliferative/antimitotic alkylating agents such asnitrogen mustards (mechlorethamine, cyclophosphamide and analogs,melphalan, chlorambucil), ethylenimines and methylmelamines(hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan,nirtosoureas (carmustine (BCNU) and analogs, streptozocin),trazenes—dacarbazinine (DTIC); antiproliferative/antimitoticantimetabolites such as folic acid analogs (methotrexate), pyrimidineanalogs (fluorouracil, floxuridine, and cytarabine), purine analogs andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine {cladribine}); platinum coordination complexes(cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones (i.e. estrogen); anticoagulants (heparin,synthetic heparin salts and other inhibitors of thrombin); fibrinolyticagents (such as tissue plasminogen activator, streptokinase andurokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab;antimigratory; antisecretory (breveldin); antiinflammatory: such asadrenocortical steroids (cortisol, cortisone, fludrocortisone,prednisone, prednisolone, 6α-methylprednisolone, triamcinolone,betamethasone, and dexamethasone), non-steroidal agents (salicylic acidderivatives i.e. aspirin; para-aminophenol derivatives i.e.acetominophen; indole and indene acetic acids (indomethacin, sulindac,and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, andketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilicacids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam,tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, goldcompounds (auranofin, aurothioglucose, gold sodium thiomalate);immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus(rapamycin), azathioprine, mycophenolate mofetil); angiogenic agents:vascular endothelial growth factor (VEGF), fibroblast growth factor(FGF) platelet derived growth factor (PDGF), erythropoetin, angiotensinreceptor blocker; nitric oxide donors; anti-sense oligionucleotides andcombinations thereof, cell cycle inhibitors, mTOR inhibitors, growthfactor signal transduction kinase inhibitors, chemical compound,biological molecule, nucleic acids such as DNA and RNA, amino acids,peptide, protein or combinations thereof.

It is to be understood that the use of the term “agent”, “therapeuticagent”, “active agent”, “drug”, “active drug”, and “pharmaceuticalagent” includes all derivatives, analogs and salts thereof and in no wayexcludes the use of two or more such agents, therapeutic agents, activeagents, drugs, active drugs, or pharmaceutical agents.

Referring now to FIG. 1, the present invention is a biodegradable and/orbioabsorbable medical device, generally designated 50, for placement orimplantation in a patient's body, wherein the medical device 50 is aself-regulating system for controlling the acidic effects ofdegradation. Additionally, biodegradable and/or bioabsorbable medicaldevice 50 is a device designed for placement within a vessel or duct,and more particularly, vasculature such as an artery or vein, as well asfor placement on, within or into an organ, and more particularly, aportion of the heart and can control the acidic effects of degradation.Even more particularly, the present invention is a medical device 50that is a device for vascular or cardiovascular use such as a stent orvalve can control the acidic effects of degradation.

Although medical device 50 is not limited to any particularconfiguration, in certain embodiments according to the presentinvention, medical device 50 has a substantially cylindricalconfiguration and is substantially hollow along its longitudinal axisand terminates at an open end at each end of its cylindricalconfiguration. Accordingly, the configuration of medical device 50 inaccordance with the present invention and as described above is bestsuited as a stent for placement within a vessel for treatment ofcardiovascular disease such as stenosis, artherosclerosis, vulnerableplaque, or ischemic heart disease or as a valve such as a heart valvefor regulating blood flow.

Medical device 50 has structure, features and components 70 thatoptionally include hoops, loops, flexible links or bridges or extensions(not shown) that are either made of a first bioabsorbable material 80itself or that are coated with a first biodegradable and/orbioabsorbable material 80, i.e. serves as a coating 70 having a firstbiodegradable and/or bioabsorbable material 80.

Medical device 50 is a self-regulating biodegradable and/orbioabsorbable system having a selective mechanism to control theundesirable effects from the degradation or erosion of any biodegradableand/or bioabsorbable material used for the device 50 such as thedegradation products and acid produced therefrom or from any acidicbyproducts produced by the degradation of the biodegradable and/orbioabsorbable material.

The first biodegradable and/or bioabsorbable material 80 is used as thebase material for structural aspects 70 of the device 50 such as hoops,loops, flexible links or bridges or extensions of the stent 50 or thehousing, flaps or other components 70 of the heart valve 50. Whenapplied as a coating 70, the first biodegradable and/or bioabsorbablematerial 80 is used as the coating material 70 to be coated over thestructural aspects of the device or stent 50 such as hoops, loops,flexible links or bridges or extensions of the stent 50 or the housing,flaps or other components of the heart valve 50.

The first biodegradable and/or bioabsorbable material 80 is a bulkerodible polymer (either a homopolymer, copolymer or blend of polymers)such as any one of the polyesters belonging to the poly(alpha-hydroxyacids) group. This includes aliphatic polyesters such poly (lacticacid); poly (glycolic acid); poly (caprolactone); poly (p-dioxanone) andpoly (trimethylene carbonate); and their copolymers and blends. Otherpolymers useful as the first bioabsorbable material include amino acidderived polymers [e.g., poly(iminocarbonates)]; phosphorous containingpolymers [e.g., poly(phosphazenes); poly (phosphoesters)] and poly(ester amide).

The rate of hydrolysis of the first biodegradable and/or bioabsorbablematerial 80 depends on the type of monomer used to prepare the bulkerodible polymer. For example, the absorption times (time to completedegradation or fully degrade) are estimated as follows:poly(caprolactone) and poly (trimethylene carbonate) takes more than 3years; poly(lactic acid) takes about 2 years; poly(dioxanone) takesabout 7 months; and poly (glycolic acid) takes about 3 months.

Absorption rates for copolymers prepared from the monomers such aspoly(lactic acid-co-glycolic acid); poly(glycolic acid-co-caprolactone);and poly(glycolic acid-co-trimethylene carbonate) depend on the molaramounts of the monomers. The degradation of the polymers is byhydrolysis and the byproducts are typically water soluble fragments suchas monomers that are used to prepare the polymers [for example, lacticacid from poly(lactic acid); glycolic acid from poly(glycolic acid)]which are metabolized by enzymatic attack then enters the kreb's cycleand excreted as carbon dioxide and water. pH values can vary based onthe type and amount of acid. If the polymer 80 absorbs slowly, then thepH values will be high as there is less amount of acid and vice versa.For example, high amount of lactic acid at a given time can have pHbetween 2 to 4.

As shown in FIGS. 1-4, a second biodegradable and/or bioabsorbablematerial 90 is used to encapsulate (shown as a cross-sectional slicetaken from a sphere) a buffering agent or a neutralizing agent 95(represented by a solid diamond shape). As best illustrated in FIGS.2-4, the second biodegradable and/or bioabsorbable material 90 is eithera surface erodible polymer or a bulk erodible polymer that is reactiveto the degradation and acidic environment or acid or inflammatoryeffects caused from the byproducts (or characteristics of byproducts)from the breakdown of the first biodegradable and/or bioabsorbablematerial 80. The second biodegradable and/or bioabsorbable material 90is either a homopolymer or copolymer or blend of polymers selected froma family of polymers that are easily degraded by acid and can includepolysaccharides (e.g., cellulose and their derivatives; starch and theirderivatives; chitin; chitosan; etc) proteins and polypeptides (e.g.,collagen) water soluble polymers; PEG based copolymers;poly(orthoesters); etc.

Accordingly, the second biodegradable and/or bioabsorbable material 90acts as a selective mechanism or triggering mechanism for releasing thebuffering agent 95 from its protected environments or encapsulatedstate. Thus, an acidic environment caused by inflammation anddegradation byproducts of the first biodegradable and/or bioabsorbablematerial 80 causes or triggers degradation of the second biodegradableand/or bioabsorbable material 90, which in turn, releases the bufferingagent 95 into the local area or local environment of the medical device50 to offset the unwanted effects on tissue (such as the inflammatoryeffects) or materials near the medical device 50. Thus, the secondbiodegradable and/or bioabsorbable material 90 (as a microparticle ornanoparticle encapsulating the buffering agent 95 in some embodimentsaccording to the present invention) regulates or controls the localacidic environment at the medical device 50. The components orbyproducts produced by degradation of the second biodegradable and/orbioabsorbable material 90, if prepared from polysaccharide, will producelow molecular weight saccharide units and if prepared from proteins willproduce amino acids as their byproducts respectively.

The encapsulation of the buffering agent 95 (FIG. 2 and FIG. 3) or thebuffering agent 95 and drug 99 (FIG. 4) (represented by a solid circularshape) can be in the form of microparticles or nanoparticles that do notadversely affect the physical properties of the device 50. Oneembodiment according to the present invention, is to encapsulate thebuffering agent 95 or buffering agent 95 and drug 99 (FIG. 4) in asecond biodegradable and/or bioabsorbable material 90 whose rate ofdegradation is either dependent upon the rate of hydrolysis or breakdown of the first polymer 80 or is dependent upon the level of acidityor acid levels in the local environment. As the first polymer 80degrades and releases acid, the second polymer 90 degrades and releasesthe buffering agent 95 (and drug 99 in the embodiment of FIG. 4) tooffset the pH of the acid produced from the first polymer 80.

Different types of buffering agents 95 can be used such as inorganicbasic fillers. Some examples of these basic compounds include calciumhydroxyapatite; carbonated apatite; tricalcium phosphate; calciumcarbonate; sodium bicarbonate; calcium phosphates; carbonated calciumphosphates; and magnesium hydroxide. Also, acid/based titratingcompounds (amine monomers); and lactate dehydrogenase (it will convertlactate in to pyruvate which is the end product of glycolysis andstarting component of Citric acid cycle) can also be used as thebuffering agent 95.

The inorganic fillers 95 will react with the acid, and neutralize theacid that is formed during the absorption of the polymers, e.g. thefirst biodegradable and/or bioabsorbable material 80 and the secondbiodegradable and/or bioabsorbable material 90. So, they behave as thebuffering agents and prevent the acid content in the immediateenvironment to be maintained at pH ranging from about 5 to about 7 andmore preferably at pH ranging from about 6 to about 7.4. The totalamount of inorganic filler or buffering agent 95 should be sufficient toneutralize the total amount of acid that is generated during theabsorption process. For example, 1 mole of calcium carbonate is neededto react with 2 mol of lactic acid (see below):CaCO₃ (solid)+2CH₃CH(OH)—COOH (aqueous)=>Ca²⁺(aq)+H₂O+CO₂ (aq)+2CH₃CH(OH)—COO— (aq)

Moreover, the self-regulating system 50 in accordance with the presentinvention, provides for a stoichiometric balance between the bufferingagent 95 and the total amount of acid released from the device 50 (dueto degradation of the first biodegradable and/or bioabsorbable polymer80 and the second biodegradable and/or bioabsorbable polymer 90 ifapplicable). Furthermore, the device 50 can be fabricated in such a waythat will allow for homogenous or preferential distribution (e.g.,layers) of the buffering agent so that there will be good control of theself-regulating system.

A typical representation of the pH control and modulation as a functionof time of the self-regulating system provided by the medical device 50in accordance with the present invention is represented in FIG. 7. Theideal pH of about 7 (normal blood pH is about 7.4) is preferable as itis neutral and will not cause any tissue inflammation (represented by ahorizontal, dashed line). When the pH begins to drop (e.g., pH of about4 in one embodiment according to the present invention) due to the acidreleased from polymer degradation of polymer 80, the buffering agent 95is released and raises the pH back to 7, i.e. to about 7.4. The trigger(triggering time T_(t)) to release the buffering agent can be atdifferent pH (for example, in other embodiments according to the presentinvention, pH ranging from about 3 to about 6) so that at a given time,the pH of the system 50 never drops to a level sufficient to cause orinduce inflammation.

As best depicted and represented in FIG. 7, a graph is used toillustrate the biodegradable action and effects attributed to themedical device 50 in accordance with the present invention.Particularly, FIG. 7 illustrates pH levels over time based ondegradation of the medical device 50 (FIG. 1) after placement orimplantation of the device 50 in a patient's body, for instance, afterthe stent 50 is deployed in a vessel in accordance with the presentinvention.

Ideally, it is desirable to maintain a neutral pH level, i.e. pH ofabout 7 (normal blood pH is about 7.4) (represented by horizontal,dashed line) or whatever the pH level was prior to placement of thedevice 50 in the tissue to be treated. As the first biodegradable and/orbioabsorbable material 80 degrades over time, acidic byproducts areformed and resulting inflammation is known to occur as a result asindicated by the solid line declining over time representing lower pH(increasing acidic environment in the local area of the device 50), theencapsulation material 90 (FIGS. 1, 2, 3, and 4) will hydrolyze at atriggering time T_(t) by acid hydrolysis and release the buffering agent95 into the local environment around the device 50.

Thus, the present invention is a medical device 50 that isself-regulating system that provides control or reduction of theinflammation caused by biodegradable and/or bioabsorbable polymers 80and 90 (FIG. 1, FIG. 2, FIG. 3, and FIG. 4) that degrades by bulkerosion and surface erosion respectively that can be used as coatings 70for metal stent 50 and as biodegradable and/or bioabsorbable polymerstent 50 (stent made entirely of biodegradable and/or bioabsorbablematerial) that are implanted or deployed in vascular systems. Theencapsulation can be micro particles or nano particles that do notadversely affect the physical properties of the device. One embodimentwould be to encapsulate a buffering agent in a second biodegradableand/or bioabsorbable material whose rate of degradation is eitherdependent upon the rate of break down of the first polymer or isdependent upon the level of acidity. As the first polymer degrades andreleases acid, the second polymer degrades and releases a bufferingagent to offset the pH of the acid from the first polymer. A typicalrepresentation of the pH control and modulation as a function of time isrepresented in FIG. 7. The ideal pH of about 7 (7.4 for normal blood) ispreferable as it is neutral and will not cause any tissue inflammation.When the pH begins to drop (e.g., 5) due to the acid released frompolymer degradation, the buffering agent is released and raises the pHback to 7 and preferably pH at about 7.4. The trigger to release thebuffering agent can be at different pH (3 to 6) so that at a given time,the pH of the system never drops to cause inflammation. There should bea stoichiometric balance between the buffering agent and the totalamount of acid released from the device. The device can be fabricated insuch a way that will allow homogenous or preferential distribution(e.g., layers) of the buffering agent so that there will be good controlof the self-regulating system.

In a three component or four component system (FIG. 1, FIG. 2, FIG. 3and FIG. 4), i.e. first polymer 80, second polymer 90 encapsulating thebuffering agent 95 and optionally the drug 99 respectively, the threecomponents or four components (when including drug 99) are formulatedtogether to create an effective self-regulating system. As the firstpolymer material 80 breaks down the second polymer material 90reacts/degrades and releases the encapsulated buffering agent 95 (andthe drug 99 in the embodiment of FIG. 4) which offset the unwantedeffects of acid and inflammation. If the first polymer material 80breaks down quickly, the buffering agent 95 is released faster (andvice-versa) to maintain a level of control on the degradation kineticsof the device 50.

In a two component or three component system (FIG. 5 and FIG. 6respectively), i.e. first polymer 80, and the buffering agent 95 andoptionally the drug 99 (FIG. 6), the two components or three components(including drug 99 as shown in FIG. 6) are formulated together to createan effective self-regulating system. As the first polymer material 80breaks down, the buffering agent 95 reacts with the local acidicenvironment which offset the unwanted effects of acid and inflammation.If the first polymer material 80 breaks down quickly, the bufferingagent 95 reacts faster (and vice-versa) to maintain a level of controlon the degradation kinetics of the device 50. In the embodimentsdepicted in FIGS. 5 and 6, the buffering agent 95 and drug 99 (FIG. 6)is/are added in the matrix of the first bioabsorbable polymer 80 so thatthe buffering agent 95 is always available to react with the acidicbyproducts.

As shown in FIG. 5 and FIG. 6, the medical device 50 can be preparedsuch that the first biodegradable and/or bioabsorbable polymer 80 hasthe neutralizing agent 95 on the backbone of the polymer. Thus, in thisembodiment according to the present invention, the medical device 50 isa self-regulating system consisting of only two components, i.e. thefirst biodegradable and/or bioabsorbable polymer 80 and the neutralizingagent 95 (FIG. 5) or a self-regulating system consisting of only threecomponents, i.e. the first biodegradable and/or bioabsorbable polymer80, the neutralizing agent 95 and the drug 99 (FIG. 6). Accordingly,when the biodegradable and/or bioabsorbable polymer 80 degrades byhydrolysis, and the neutralizing agent 95 (chemical entity) is released(triggered by the acid formation) at the triggering time T_(t) and willneutralize the acid and thereby raise the pH of the local environmentback up to neutral, i.e. pH of about 7 as shown in FIG. 7 and preferablyto pH of about 7.4 for those tissues having normal blood level pH ofabout 7.4. The advantage of this approach is that the acid and theneutralizing agent will be at close proximity and therefore the pHregulation can be tightly controlled. Also, the acid used to synthesizethe polymer can be of a pH that is not detrimental to tissues. Moreover,as the biodegradable and/or bioabsorbable polymer 80 degrades, drug 99is dispersed or released from the polymer 80 and device 50 therebyproviding therapy to the tissue at the local environment or evensystemically if desired.

A method of formulating the biomaterial structure or coating 70 of themedical device 50 using the first biodegradable and/or bioabsorbablematerial 80 and the second biodegradable and/or bioabsorbable material90 and the second biodegradable and/or bioabsorbable material 90together with the buffering agent 95 to encapsulate the buffering agent95 is described in greater detail later below. This method is alsoapplicable for combining with a therapeutic agent or drug 99(represented by a solid circular shape) which can be mixed together withthe polymer material of the device structure 70 (when the device 50 ismade of the first biodegradable and/or bioabsorbable material 80 itself)such as shown in FIG. 3 or mixed with the buffering agent 95 and thesecond biodegradable and/or bioabsorbable material 90 for encapsulatingboth the buffering agent 90 together with the drug 99 especially when itis important to protect the stability or efficacy of the drug 99, i.e.neutralize or offset the detrimental effects of local acid environmentand acidic byproducts on the structure or conformation of the drug 99.

It will be appreciated by those skilled in the art that the relativeamounts of the first biodegradable and/or bioabsorbable material 80 tothe second biodegradable and/or bioabsorbable material 90 and relativeamounts of the buffering agent 95 and/or drug 99 to the firstbiodegradable and/or bioabsorbable material 80 and/or the secondbiodegradable and/or bioabsorbable material 90 in the composites of thepresent invention (represented in the embodiments depicted in FIGS. 2-6respectively) will depend upon various parameters including, inter alia,the levels of strength, stiffness, and other physical and thermalproperties, absorption and resorption rates, setting and hardeningrates, deliverability, etc., which are required. The desired propertiesof the composites of the embodiments of the present invention and theirlevel of requirement will depend upon the body structure area or anatomywhere the medical device 50 and/or buffering agent 95 and/or drug 99is/are needed.

The composites of the present invention can be manufactured in thefollowing process as an example. The preformed polymers, i.e. the firstbiodegradable and/or bioabsorbable material 80 and the secondbiodegradable and/or bioabsorbable material 90 and the bufferingmaterial 95 and optionally the drug 99 and any of its requiredexcipients are individually charged into a conventional mixing vesselhaving a conventional mixing device mounted therein such as an impelleri.e. the second material 90 and the buffering material 95 and drug 99(if included) are first mixed forming encapsulated buffering material 95and drug 99 (if included). The second biodegradable and/or bioabsorbablematerial polymer(s) 90 and the buffering agent 95 and optionally thedrug 99 are mixed at a temperature suitable for the given polymers as isknown in this field until uniformly dispersion is obtained in order toensure that the buffering agent 95 and drug 99 when optionally includedas part of the encapsulation by the second biodegradable and/orbioabsorbable polymer 90 (FIG. 4). Then, the mixture may be furtherprocessed by removing it from the mixing device, cooling to roomtemperature, grinding, and drying under pressures below atmospheric atelevated temperatures for a period of time. Typical encapsulationprocesses can be used which can include spray drying, coacervation, etc.Alternatively, encapsulation can be prepared by extruding, tray drying,drum drying or the like to form solids which are then ground to thedesired particle size. The encapsulated buffering agent 95 and drug 99(if included) is then mixed with the first biodegradable and/orbioabsorbable material 80 using suitable temperatures and processessteps such as those mentioned above and below.

The same process as outlined above is used when it is desirable to havejust the first biodegradable and/or bioabsorbable material 80 as thematerial for the device structure or a coating 70 for the devicestructures (without the use of any second biodegradable and/orbioabsorbable material 90) together with the buffering agent 95 (FIG. 5)or together with the buffering agent 95 and the drug 99 (FIG. 6).

In addition to the above manufacturing method, the composites can beprepared by a one-step process by charging the buffering agent 95 andoptionally the drug 99 to a reaction vessel which contains thejust-formed polymers of the second biodegradable and/or bioabsorbablepolymer 90 (when encapsulation is desired) or the first biodegradableand/or bioabsorbable polymer 80 (when only one biodegradable and/orbioabsorbable polymer is desired complexed together with the bufferingagent 95 or the buffering agent and drug 99 such as depicted in FIG. 5and FIG. 6 respectively).

It is important to note that all processing techniques used for thepresent invention will be at sufficient temperatures that will notdegrade the drug 99, the buffering agent 95, the first material 80 andthe second material 90.

As mentioned above, articles such as the medical devices 50 themselvesmay be molded from the composites of the present invention by use ofvarious conventional injection and extrusion processes and moldingequipment equipped with dry nitrogen atmospheric chamber(s) atacceptable temperatures.

The composites of this invention can be melt processed by numerousconventional methods to prepare a vast array of useful devices 50. Thesematerials can be injection or compression molded to make implantable,biodegradable and/or bioabsorbable medical and surgical devices,especially biodegradable and/or bioabsorbable vascular devices such asstents including drug eluting stents and biodegradable and/orbioabsorbable cardiovascular devices such as heart valves includingheart valves that are capable of eluting drugs 99.

Alternatively, the composites can be extruded (melt or solution) toprepare fibers and films. The filaments thus produced may be spun asmultifilament yarn, or meshes, knitted or woven, and formed byconventional molding techniques into reinforced devices 50 and utilizedwhere it is desirable that the structure have high tensile strength anddesirable levels of compliance and/or ductility. Useful embodimentsinclude preformed valves or stents for areas where vessels and hearttissue including heart valves are have been or are easily damaged orsurgically removed.

As mentioned above, the composites of the present invention may also beused to coat substrates, i.e. serve as a biodegradable and/orbioabsorbable polymer coating 70 or a biodegradable and/or bioabsorbabledrug eluting polymer coating 70 (FIG. 3 and FIG. 6), such asbiocompatible substrates such as meshes, the various structuralcomponents and elements of medical devices, for example, the hoops,loops, flexible links or bridges or extensions of the stent 50 or thehousing, flaps or other components of the heart valve 50, etc. Thecoatings 70 would be made by utilizing liquid composites of the presentinvention which would then be applied to the substrate by conventionalcoating techniques such as dipping, spraying, brushing, roller coating,etc.

Additionally, the composites can be molded to form films which areparticularly useful for those applications where a drug delivery matrixin tissue (e.g., growth factors) is desired, for example for achievingangiogenesis and/or myogenesis in cardiovascular tissue including thevessels, myocardium, endocardium and epicardium or pericardium of theheart.

Furthermore, the composites of the present invention can be formed intofoams, with open or closed cells, which are useful for applicationswhere a high rate of tissue ingrowth is required such as remodelingheart tissue for inducing myogenesis or angiogenesis for treatment ofcardiovascular disease such as congestive hear failure (CHF) or ischemicheart disease.

In more detail, the surgical and medical uses of the filaments, films,foams, molded articles, and injectable devices of the present inventioninclude, but are not necessarily limited to vessels or heart tissue. Themedical device 50 in accordance with the present invention can also beused for devices such as clamps, screws, and plates; clips; staples;hooks, buttons, and snaps; preformed tissue substitutes such asprosthetics or grafts, injectable polymers; vertebrae discs; anchoringdevices such as suture anchors; septal occlusion devices; injectabledefect fillers; preformed defect fillers; bone waxes; cartilagereplacements; spinal fixation devices; drug delivery devices; foams withopen or closed cells, and others.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variations and modifications maybe made herein, in accordance with the inventive principles disclosed,without departing from the scope of the invention.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes and substitutions will now occur to those skilled inthe art without departing from the invention. Accordingly, it isintended that the invention be limited only by the spirit and scope ofthe appended claims.

1. A medical device for placement at a site in a patient's body and forcontrolling pH levels at the site in the patient's body, the devicecomprising: one or more structural components made of a firstbiodegradable and/or bioabsorbable material; a buffering agent; and atleast one second biodegradable and/or bioabsorbable material on or inthe one or more structural components, the at least one secondbiodegradable and/or bioabsorbable material encapsulating the bufferingagent, the buffering agent being dispersed from the at least one secondbiodegradable and/or bioabsorbable material in response to hydrolysis ofthe first biodegradable and/or bioabsorbable material.
 2. The medicaldevice according to claim 1, wherein the first biodegradable and/orbioabsorbable material is a bulk erodible polymer that is either ahomopolymer, a copolymer or a blend of polymers.
 3. The medical deviceaccording to claim 2, wherein the at least one second biodegradableand/or bioabsorbable material is a surface erodible polymer.
 4. Themedical device according to claim 2, wherein the at least one secondbiodegradable and/or bioabsorbable material is a bulk erodible polymer.5. The medical device according to claim 2, wherein the bulk erodiblepolymer is a polyester.
 6. The medical device according to claim 5,wherein the polyester belongs to the poly(alpha-hydroxy acids) group. 7.The medical device according to claim 6, wherein the polyester is analiphatic polyester.
 8. The medical device according to claim 7, whereinthe aliphatic polyester is selected from the group consisting of poly(lactic acid), poly (glycolic acid), poly (caprolactone), poly(p-dioxanone) and poly (trimethylene carbonate).
 9. The medical deviceaccording to claim 2, wherein the bulk erodible polymer is an amino acidderived polymer selected from the group consisting ofpoly(iminocarbonates), phosphorous containing polymers,poly(phosphazenes), poly(phosphoesters) and poly(ester amide).
 10. Themedical device according to claim 1, wherein the at least one secondbiodegradable and/or bioabsorbable material is a either a homo polymer,a copolymer or a blend of polymers.
 11. The medical device according toclaim 10, wherein the at least one second biodegradable and/orbioabsorbable material is a polymer selected from the group consistingof polysaccharides, poly(orthoesters), proteins, water soluble polymersand PEG based copolymers.
 12. The medical device according to claim 11,wherein the at least one second absorbable material is in the form of amicroparticle.
 13. The medical device according to claim 11, wherein theat least one second biodegradable and/or bioabsorbable material is inthe form of a nanoparticle.
 14. The medical device according to claim 1,further comprising a drug encapsulated by the at least one secondbiodegradable and/or bioabsorbable material.
 15. The medical deviceaccording to claim 1, further comprising a drug with the firstbiodegradable and/or bioabsorbable material.
 16. The medical deviceaccording to claim 1, wherein the buffering agent is selected from thegroup consisting of calcium hydroxyapatite, carbonated apatite,tricalcium phosphate, calcium carbonate, sodium bicarbonate, calciumphosphates, carbonated calcium phosphates, magnesium hydroxide, aminemonomers, and lactate dehydrogenase.
 17. The medical device according toclaim 1, wherein the buffering agent is dispersed from the at least onesecond biodegradable and/or bioabsorbable material at pH<7.4.
 18. Themedical device according to claim 17, wherein the buffering agent isdispersed from the at least one second biodegradable and/orbioabsorbable material at pH ranging from about 3 to about
 6. 19. Themedical device according to claim 18, wherein the buffering agent isdispersed from the at least one second biodegradable and/orbioabsorbable material at pH of about
 5. 20. The medical deviceaccording to claim 17, wherein the buffering agent raises pH at the siteafter being dispersed from the at least one second biodegradable and/orbioabsorbable material.
 21. The medical device according to claim 20,wherein the buffering agent raises pH to about 7.4 at the site afterbeing dispersed from the at least one second biodegradable and/orbioabsorbable material.
 22. The medical device according to claim 1,wherein the device is a stent.
 23. The medical device according to claim1, wherein the device is a valve.
 24. The medical device according toclaim 1, wherein the device is selected from the group consisting ofclamps, screws, plates, clips, staples, hooks, buttons, snaps,prosthetics, grafts, injectable polymers, vertebrae discs, anchoringdevices, suture anchors, septal occlusion devices, injectable defectfillers, preformed defect fillers, bone waxes, cartilage replacements,spinal fixation devices, drug delivery devices and foams.
 25. A medicaldevice for placement at a site in a patient's body and for controllingpH levels at the site in the patient's body, the device comprising: oneor more structural components having a coating thereon, the coating madeof a first biodegradable and/or bioabsorbable material; a bufferingagent; and at least one second biodegradable and/or bioabsorbablematerial on or in the coating on the one or more structural components,the at least one second biodegradable and/or bioabsorbable materialencapsulating the buffering agent, the buffering agent being dispersedfrom the at least one second biodegradable and/or bioabsorbable materialin response to hydrolysis of the first biodegradable and/orbioabsorbable material.
 26. The medical device according to claim 25,wherein the first bioabsorbable material is a bulk erodible polymer thatis either a homopolymer, a copolymer or a blend of polymers.
 27. Themedical device according to claim 26, wherein the at least one secondbiodegradable and/or bioabsorbable material is a surface erodiblepolymer.
 28. The medical device according to claim 26, wherein the atleast one second biodegradable and/or bioabsorbable material is a bulkerodible polymer.
 29. The medical device according to claim 26, whereinthe bulk erodible polymer is a polyester.
 30. The medical deviceaccording to claim 29, wherein the polyester belongs to thepoly(alpha-hydroxy acids) group.
 31. The medical device according toclaim 30, wherein the polyester is an aliphatic polyester.
 32. Themedical device according to claim 31, wherein the aliphatic polyester isselected from the group consisting of poly (lactic acid), poly (glycolicacid), poly(caprolactone), poly(p-dioxanone) and poly(trimethylenecarbonate).
 33. The medical device according to claim 26, wherein thebulk erodible polymer is an amino acid derived polymer selected from thegroup consisting of poly(iminocarbonates), phosphorous containingpolymers, poly(phosphazenes), poly(phosphoesters) and poly(ester amide).34. The medical device according to claim 25, wherein the at least onesecond biodegradable and/or bioabsorbable material is a either ahomopolymer, a copolymer or a blend of polymers.
 35. The medical deviceaccording to claim 34, wherein the at least one second biodegradableand/or bioabsorbable material is a polymer selected from the groupconsisting of polysaccharides, poly(orthoesters), proteins, watersoluble polymers and PEG based copolymers.
 36. The medical deviceaccording to claim 35, wherein the at least one second biodegradableand/or bioabsorbable material is in the form of a microparticle.
 37. Themedical device according to claim 35, wherein the at least one secondbiodegradable and/or bioabsorbable material is in the form of ananoparticle.
 38. The medical device according to claim 25, furthercomprising a drug encapsulated by the at least one second biodegradableand/or bioabsorbable material.
 39. The medical device according to claim25, further comprising a drug with the first biodegradable and/orbioabsorbable material.
 40. The medical device according to claim 25,wherein the buffering agent is selected from the group consisting ofcalcium hydroxyapatite, carbonated apatite, tricalcium phosphate,calcium carbonate, sodium bicarbonate, calcium phosphates, carbonatedcalcium phosphates, magnesium hydroxide, amine monomers, and lactatedehydrogenase.
 41. The medical device according to claim 25, wherein thebuffering agent is dispersed from the at least one second biodegradableand/or bioabsorbable material at pH<7.4.
 42. The medical deviceaccording to claim 41, wherein the buffering agent is dispersed from theat least one second biodegradable and/or bioabsorbable material at pHranging from about 3 to about
 6. 43. The medical device according toclaim 42, wherein the buffering agent is dispersed from the at least onesecond biodegradable and/or bioabsorbable material at pH of about
 5. 44.The medical device according to claim 41, wherein the buffering agentraises pH at the site after being dispersed from the at least one secondbiodegradable and/or bioabsorbable material.
 45. The medical deviceaccording to claim 44, wherein the buffering agent raises pH to about7.4 at the site after being dispersed from the at least one secondbiodegradable and/or bioabsorbable material.
 46. The medical deviceaccording to claim 25, wherein the device is a stent.
 47. The medicaldevice according to claim 25, wherein the device is a valve.
 48. Themedical device according to claim 25, wherein the device is selectedfrom the group consisting of clamps, screws, plates, clips, staples,hooks, buttons, snaps, prosthetics, grafts, injectable polymers,vertebrae discs, anchoring devices, suture anchors, septal occlusiondevices, injectable defect fillers, preformed defect fillers, bonewaxes, cartilage replacements, spinal fixation devices, drug deliverydevices and foams.